Evaluation of Ultevursen Efficacy, Safety, and Tolerability in Retinitis Pigmentosa Patients with USH2A Exon 13 Mutations: A Two-Year Randomized, Sham-Controlled Study

Trial ID: 2024-515199-10-00
Protocol: SB-421a-006
Sponsor: Laboratoires Thea

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Diseases & Conditions

Retinitis pigmentosa

Objectives

The primary objective of this study is to evaluate the **efficacy** of Ultevursen after 24 months of treatment in subjects with **Retinitis Pigmentosa** due to mutations in exon 13 of the USH2A gene. This objective is clinically relevant as it aims to determine the therapeutic potential of Ultevursen in slowing or halting the progression of this degenerative retinal disease, which can lead to significant visual impairment.

Secondary objectives include:

To evaluate the efficacy of other endpoints and/or timepoints, providing a comprehensive understanding of the treatment's impact over different measures and durations.
To evaluate the **safety** and **tolerability** of Ultevursen, ensuring that the treatment is not only effective but also safe for long-term use.
To evaluate the systemic exposure of Ultevursen, which is crucial for understanding the pharmacokinetics and potential systemic effects of the drug.

Participants

The clinical trial involves a total of **54 participants** diagnosed with **Retinitis Pigmentosa**. The study population includes both male and female subjects, with an age range spanning from 8 years to adults over 18 years. Participants were selected based on specific inclusion criteria, ensuring they are either adults capable of providing informed consent or minors able to provide age-appropriate assent with parental permission. The trial includes individuals with a molecular diagnosis of biallelic disease-causing variants in the USH2A gene, with at least one variant located on exon 13. Participants are required to have a baseline visual acuity of at least 55 letters based on the ETDRS scale and must not have visually significant ocular media opacities. The study population is characterized by a clinical presentation consistent with either Usher syndrome type 2 or non-syndromic Retinitis Pigmentosa, as determined by ophthalmic, audiologic, or vestibular examinations. Both eyes of the participants must exhibit a clearly visible and measurable ellipsoid zone width of at least 2.5 mm in both horizontal and vertical scans. The trial includes a vulnerable population, and all participants are expected to comply with the study protocol, attend required visits, and complete all assessments as determined by the investigator.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, sham-controlled study to evaluate the efficacy, safety, and tolerability of **ultevursen** in subjects with **Retinitis Pigmentosa** due to mutations in exon 13 of the USH2A gene. The trial will span a duration of two years, with the primary objective being to assess efficacy after 24 months of treatment. Participants will be randomly assigned to receive either the active treatment, ultevursen, administered as a solution for injection via **intravitreal use**, or a sham procedure that mimics the active injection without globe penetration.

The study will commence with an inclusion (screening) visit to determine eligibility based on specific criteria, including age, visual acuity, and genetic confirmation of the USH2A mutation. Following successful screening, participants will undergo baseline assessments before the initiation of treatment. Study visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. Key assessments will include changes in retinal sensitivity, visual acuity, and structural changes in the retina as measured by spectral-domain optical coherence tomography (SD-OCT).

Participants are expected to be involved in the study for the entire two-year duration unless conditions arise that necessitate early termination. Such conditions may include the occurrence of significant adverse events, non-compliance with study procedures, or withdrawal of consent. The end-of-study visit will involve comprehensive assessments to evaluate the long-term effects of the treatment. The trial aims to provide valuable insights into the potential benefits of ultevursen for individuals affected by this genetic form of retinitis pigmentosa.

Treatment

The clinical trial involves the administration of **Ultevursen**, an experimental medication formulated as a **solution for injection**. Ultevursen is an antisense oligonucleotide targeting exon 13 in the USH2A gene, specifically designed for the treatment of **Retinitis Pigmentosa** due to mutations in this exon. The active substance, Ultevursen, is derived from nucleic acid and is administered via **intravitreal use**. The dosing regimen includes a maximum daily dose of 60 micrograms, with a total maximum dose of 180 micrograms over a treatment period of 18 months. The pharmaceutical product is provided by Laboratoires Thea and is identified by the sponsor product code QR-421a.

In addition to the experimental treatment, the study includes a sham procedure as a comparator. Participants in the sham group will undergo a procedure that closely mimics the active injection but without penetration of the globe. This approach is intended to maintain the double-masked nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment allocation. The sham procedure serves as a placebo control to evaluate the efficacy, safety, and tolerability of Ultevursen over the course of the two-year study.

Efficacy

The efficacy of the investigational product, **ultevursen**, in the treatment of **Retinitis Pigmentosa** due to mutations in exon 13 of the USH2A gene will be assessed through a series of predefined endpoints. The primary endpoint is the annualized percent change from baseline in ellipsoid zone (EZ) width as measured by spectral-domain optical coherence tomography (SD-OCT) up to Month 24. Secondary endpoints include changes in retinal sensitivity measured by static perimetry (SP) and microperimetry (MP) with topographic analysis (Hill of Vision [HoV]), changes from baseline in low luminance visual acuity (LLVA) and best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, and percent changes from baseline in EZ area and width by SD-OCT. Additional assessments involve changes in virtual visual maze performance score using the Mobility Standardized Test in Virtual Reality (MOSTVR), dark-adapted full-field stimulus threshold (FST) testing, and various patient-reported outcomes (PROs) for subjects aged 13 years and older, including the Michigan Retinal Degeneration Questionnaire (MRDQ) and the Michigan Vision-Related Anxiety Questionnaire (MVAQ).

Efficacy parameters will be evaluated at Months 12 and 24, unless otherwise specified. The study will utilize validated tools and instruments such as the ETDRS chart for visual acuity assessments and SD-OCT for imaging. The collection and analysis of these parameters will be conducted in accordance with the study protocol to ensure the reliability and validity of the results. The trial is designed to provide comprehensive data on the efficacy of ultevursen over a two-year period, contributing to the understanding of its potential benefits in managing this genetic condition.

Inclusion and Exclusion Criteria

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Inclusion Criteria

An adult (≥18 years) willing and able to provide informed consent for participation prior to performing any study related procedures OR A minor (8 to <18 years) able to provide age-appropriate assent for study participation with a parent or legal guardian willing and able to provide written permission for the subject’s participation prior to performing any study related procedures.
An adult willing to comply with the protocol, follow study instructions, attend study visits as required and willing and able to complete all study assessments, in the opinion of the Investigator. OR A minor able to complete all study assessments and comply with the protocol and has a parent or caregiver willing and able to follow study instructions and attend study visits with the subject as required, in the opinion of the Investigator.
Both eyes exhibit clinical presentation consistent with RP involving Usher syndrome type 2 or NSRP based on ophthalmic, audiologic, or vestibular examinations. At screening, the Investigator will make the clinical diagnosis of “Usher syndrome type 2a,” defined as RP with congenital hearing loss, or “non-syndromic RP,” defined as RP without congenital hearing loss.
A molecular diagnosis of biallelic disease causing variants (pathogenic or likely pathogenic) in the USH2A gene where at least one of the variants is located on exon 13. A historic genotyping report from a certified laboratory is acceptable with Sponsor approval.
Clearly visible and measurable EZ width of ≥2.5 mm in both horizontal and vertical scans in both eyes as measured by SD-OCT and based on the assessment of the CRC.
BCVA ≥55 letters based on ETDRS (equivalent to 20/80 based on Snellen notation, or logarithm of the minimum angle of resolution [logMAR] +0.6) in both eyes.
Impairment of VF as assessed by SP with a mean sensitivity >4 decibels (dB) and <25 dB measured by a V4e target size in the TE.
Mean sensitivity >2 dB as determined by MP in the TE.
No limitations to SD-OCT image collection that would prevent high-quality, reliable images from being obtained in both eyes, as determined by the Investigator.
During the screening period, the difference of BCVA letters (based on ETDRS) from 2 measurements taken separately will need to be within 10 letters. After 3 attempts of the BCVA measurement, if a reliable baseline cannot be obtained, the eligibility of the subject will be determined in consultation with the Medical Monitor.
Symmetry of baseline disease in both eyes, defined as the mean BCVA (based on ETDRS) of one eye within ≤10 letters of the mean BCVA of the other eye at screening. If this is not present, the Investigator should discuss the case with the Medical Monitor to decide whether it is appropriate for the subject to participate in the study. For purposes of determining symmetry, the mean BCVA for each eye will be calculated using all BCVA measures obtained during the screening period.
At screening, reliable measurements in MP and SP as described in the Study Reference Manual.
No visually significant ocular media opacities and adequate pupillary dilation to permit good quality retinal visibility or imaging in either eye, as assessed by the Investigator.
Non-pregnant and non-breastfeeding subjects. Women of childbearing potential (WOCBP) and fertile males must comply with using highly effective methods of contraception (see Section 14.2 for definitions of WOCBP and fertile males and details on highly effective contraception methods). Women of non-childbearing potential may be included without the use of adequate birth control, provided they meet the entry criteria for the study.

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Exclusion Criteria

Presence of additional non-exon 13 USH2A pathogenic or likely pathogenic variant on the USH2A allele carrying the exon 13 mutation in subjects who have one exon 13 disease causing variant and one non-exon 13 disease causing variant.
Presence of additional non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who have biallelic exon 13 mutations.
Presence of pathogenic or likely pathogenic variants in genes (other than the USH2A gene) which are known to be associated with other inherited retinal degenerative diseases or syndromes. Specifically, the presence of homozygous or compound heterozygous known disease-causing mutations in other genes involved in recessive retinal dystrophies, or the confirmed presence of a known single disease-causing variant in genes involved in dominant, X-linked, or mitochondrial retinal dystrophy genes is exclusionary.
Any contraindication to IVT injection according to the Investigator’s clinical judgment and the American Academy of Ophthalmology (Avery 2014). This includes any active or suspected intraocular inflammation or active or suspected ocular or periocular infection in either eye.
At screening, the EZ horizontal or vertical width are outside the field of the SD-OCT scan based on the assessment of the CRC.
Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities) which, in the opinion of the Investigator and with concurrence of the Medical Monitor, may either put the subject at risk because of participation in the study, may impact the subject’s ability to participate in the study, or may interfere with assessment of efficacy and safety in the study.
Presence of unstable concurrent cystoid macular edema (CME), or subject started on (or changed dose of) topical or systemic carbonic anhydrase inhibitor treatment in the 3 months prior to enrollment. CME is allowed if stable for 3 months (with or without treatment). However, stable CME that disrupts the EZ width measurement, as determined by CRC, is an exclusion.
Receipt of any prior intraocular or periocular surgery or planned intraocular surgery or procedure during the study. Subjects may be considered for inclusion if there are no clinically significant complications of surgery present and following approval by the Medical Monitor.
Receipt of any IVT injection prior to study entry. However, subjects who have received a prior IVT injection may be considered for inclusion following approval by the Medical Monitor.
History or presence of ocular herpetic disease (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye.
Presence of any of the following lens opacities in the TE based on the Age-Related Eye Disease Study (AREDS) lens grading scale: cortical opacity ≥+2, posterior subcapsular opacity ≥+2, or a nuclear sclerosis ≥+2, and which are: 1) clinically significant in the opinion of the Investigator, 2) would adequately prevent clinical and photographic evaluation of the retina.
History of amblyopia in the TE that has resulted in vision loss, in the opinion of the Investigator.
Presence of significant keratopathy or any other media or corneal opacity that would cause scattering of light or alter visual function, especially in low luminance conditions in the TE.
A history of glaucoma or an IOP greater than 24 mmHg in the TE that is not controlled with medication or surgery at the time of informed consent.
Use of any investigational drug or device within 90 days or 5 half-lives of Day 1, whichever is longer, or plans to participate in another study of a drug or device during the study.
Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.
Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
Current chronic treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to steroid implants, chronic systemic steroids, cytostatics, interferons, tumor necrosis factor (TNF)-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). Subjects who have been treated on a short course of systemic steroids within the past 12 months or who require intermittent use of topical steroids may be considered for inclusion following approval by the Medical Monitor.
Current use of medications known to be toxic to the lens, retina, or optic nerve (e.g., deferoxamine, chloroquine/hydroxychloroquine [Plaquenil®], tamoxifen, phenothiazines, ethambutol, digoxin, and aminoglycosides).
History of malignancy within 5 years prior to Screening, except adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Yet Recruiting	30 Apr 2025	6
Germany	Not Yet Recruiting	30 Apr 2025	3
Italy	Not Yet Recruiting	30 Apr 2025	6
The Netherlands	Not Yet Recruiting	30 Apr 2025	—
Netherlands	—	—	6